• Nina Wyss, Fiamma Berner, Vincent Walter, Ann-Kristin Jochum, Mette T Purde, Marie-Therese Abdou, Tobias Sinnberg, Kathrin Hofmeister, Oltin T Pop, Hasan AliOmarOInstitute of Immunobiology.Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland., Jens Bauer, Hung-Wei Cheng, Mechthild Lütge, Niklas Klümper, Stefan Diem, Zeynep Kosaloglu-Yalcin, Yizheng Zhang, Laura Sellmer, Boris Macek, Julia Karbach, David König, Heinz Läubli, Lars Zender, Britta S Meyer, Christoph Driessen, Christian M Schürch, Wolfram Jochum, Teresa Amaral, Lucie Heinzerling, Antonio Cozzio, Ahmed N Hegazy, Tino Schneider, Martin H Brutsche, Alessandro Sette, Tobias L Lenz, Juliane Walz, Hans-Georg Rammensee, Martin Früh, Elke Jäger, Burkhard Becher, Amanda Tufman, Nicolas Nuñez, Markus Joerger, and Lukas Flatz.
• Institute of Immunobiology.
• Am. J. Respir. Crit. Care Med. 2024 Oct 1; 210 (7): 919930919-930.

AbstractRationale: Immune checkpoint inhibitor (ICI)-related pneumonitis is a serious autoimmune event affecting as many as 20% of patients with non-small-cell lung cancer (NSCLC), yet the factors underpinning its development in some patients and not others are poorly understood. Objectives: To investigate the role of autoantibodies and autoreactive T cells against surfactant-related proteins in the development of pneumonitis. Methods: The study cohort consisted of patients with NSCLC who provided blood samples before and during ICI treatment. Serum was used for proteomics analyses and to detect autoantibodies present during pneumonitis. T-cell stimulation assays and single-cell RNA sequencing were performed to investigate the specificity and functionality of peripheral autoreactive T cells. The findings were confirmed in a validation cohort comprising patients with NSCLC and patients with melanoma. Measurements and Main Results: Across both cohorts, patients in whom pneumonitis developed had higher pretreatment levels of immunoglobulin G autoantibodies targeting surfactant protein (SP)-B. At the onset of pneumonitis, these patients also exhibited higher frequencies of CD4+ IFN-γ-positive SP-B-specific T cells and expanding T-cell clonotypes recognizing this protein, accompanied by a proinflammatory serum proteomic profile. Conclusions: Our data suggest that the cooccurrence of SP-B-specific immunoglobulin G autoantibodies and CD4+ T cells is associated with the development of pneumonitis during ICI therapy. Pretreatment levels of these antibodies may represent a potential biomarker for an increased risk of developing pneumonitis, and on-treatment levels may provide a diagnostic aid.

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